The emergence of 3'-azido-3'- deoxythymidine (AZT) as an anti-HIV agent has demonstrated the biological importance of nucleosides missing a 3'-hydrol group. Moreover, the discovery that 2',3'-dideoxy (dd) and 2',3'-didehydro-2',3'-dideoxy (D4) nucleoside analogs exhibit potent antiviral activity has spurred both the search for superior therapeutic agents and the development of high-yielding process for the synthesis of such nucleosides. See, for example, De Clercq, E. J. Chemother., Supp. A 1989, 23, 35.; Balzarini, et al., Mol. Pharmacol. 1987, 32, 162.
As the result of systematic modifications at both the sugar and base moieties, a number of 2',3'-dideoxynucleoside derivatives have been approved for clinical use against viral infection. These include D-.beta.-ddI (2',3'-dideoxyinosine), D-.beta.-ddC (2',3'-dideoxycytidine, Mitsuya and Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83, 1911) and D-.beta.-D4T (2',3'-didehydro-2',3'-dideoxythymidine, Mansuri, et al., J. Med Chem. 1989, 32, 461). Recently, a number of the L-configuration nucleoside analogs, the enantiomers of the natural D-nucleosides, have emerged as potent antiviral agents against HBV and HIV. These analogs include (-)SddC (3TC) [(2-hydroxymethyl-1,3-oxathiolan-4-yl)cytosine]; (-)FSddC (-FTC) [(2-hydroxymethyl-1,3-oxathiolan-4-yl)-5-fluorocytosine, Chang, C-N., et al., J. Biol. Chem., 1992, 267, 13938-13942 and Doong, S-L. Et al., Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 8495-8499]; .beta.-L-ddC (.beta.-L-2',3'-dideoxycytidine, Lin, T-S., et al., Tetrahedron Lett. 1994, 35, 3477 and Lin, T-S., et al., J. Med. Chem. 1994, 37, 798-803); .beta.-L-FddC (.beta.-L-3-L-5-Fluoro-2',3'-dideoxycytidine, Lin, T-S., et al., J. Med. Chem. 1994, 37, 798-803); and .beta.-L-FD4C (.beta.-L-5-fluoro-2',3'-dideoxy-2',3'-didehydrocytidine, Lin, T-S. et al., J. Med. Chem. 1996, 39, 1757.
When compared with their counterparts with D-configuration, the unnatural L-nucleosides mentioned above are endowed with greater antiviral activity (especially against HBV and HIV, for example) and reduced host toxicity in terms of inhibition of cell growth and mitochondrial DNA synthesis. Among these L-nucleosides discussed here, .beta.-L-FD4C was found to be most active against HBV (Lin, et al., J. Med. Chem., 1996, 39, 1757). In fact, .beta.-L-FD4C was about 10-fold more potent against HBV than (-) SddC (3TC), which has been approved recently by the FDA for use in combination therapy against HIV and HBV. The superb antiviral activity observed with .beta.-L-FD4C and .beta.-L-FddC, as well as the clear pharmaceutical potential of other nucleoside analogs, warrant further development of these pharmacological agents as prime candidates for use as anti-viral, including anti-HBV and anti-HIV agents as well as for other uses.
The first synthesis and the antiviral activity assessment of .beta.-L-FD4C was achieved by a group of scientists at Yale University under the supervision of Drs. Lin and Cheng (J. Med. Chem., 1996, 39, 1757). The Yale synthesis consisted of a twelve-step sequence with an overall yield of less than 0.74%. Perhaps the least efficient step in the sequence was the introduction of 5-fluorouracil using a trans-N-glycosylation reaction, which provided only about 10% of the desired .beta.-anomer intermediate. Although this research conducted at Yale represents a major breakthrough in the search of potent antiviral nucleosides with minimal host toxicity, the initial low-yielding synthesis is not amenable for scale-up. Therefore, in order to prepare large amounts of .beta.-L-FD4C for scale-up, clinical testing and ultimately, commercialization, a much more efficient synthesis is desired.